The new frontier of epigenetic drugs: an Italian study against cancer is underway

In Siena, the path of epigenetics continues to be pursued to make tumors more visible by the immune system. And, therefore, to make immunotherapy more effective.

The pioneer of this strategy is the group of the NIBIT Foundation and the Immuno-Oncology Center (CIO) at the Santa Maria alle Scotte Polyclinic in Siena, both headed by oncologist Michele Maio. In fact, a new study is starting in the Tuscan city: the first treatment is scheduled for today, to the first patient, of the first treatment that combines two immunotherapies (ipilimumab and nivolumab, already available) with a new epigenetic oral drug (ASTX727).

The study, called NIBIT-ML1 and supported by the Airc Foundation, will be carried out in collaboration with 5 other Italian research centers (INT Milan, IST Genoa, University of Florence, Naples and Sassari) and will concern patients with melanoma or advanced lung cancer who they do not respond to immunotherapy.

Objective: to increase the response to immunotherapy

Immunotherapy drugs (immune checkpoint inhibitors) have revolutionized the treatment of many cancers, notably (but not limited to) melanoma, lung cancer and kidney cancer. About half of the patients, however, do not respond to this strategy and for this reason various strategies are being tested that can make the tumor more immunogenic, that is, “visible” for the immune system. One of these strategies concerns the so-called epigenetic drugs, which are able, that is, to make chemical changes to the DNA and modulate the expression of genes.

From idea to experimentation

Thanks to research from the NIBIT Foundation, it has been discovered that epigenetic drugs can act as immunomodulators. Hence the scientific rationale and the first phase 1 clinical study, the results of which were presented at the Asco congress in 2019. The new study will evaluate the triple combination.

“Our goal – explains Anna Maria Di Giacomo, associate professor of Medical Oncology at the University of Siena, head of the Phase I / II clinical trials program of the IOC and coordinator of the study – will be to evaluate the effectiveness of the combination. of two immunotherapy drugs in combination with a new demethylating drug in patients with metastatic melanoma or lung cancer in progression after previous therapy with antibodies directed against PD-1 / PD-L1 “.

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The importance of non-profit research

Studying in depth the mechanisms that the tumor puts in place to evade the immune response is of fundamental importance. Being able to decipher them represents the starting point for the development of new strategies to be associated with immunotherapy, as recalled by Michele Maio, professor of Oncology at the University of Siena, director of the Immuno-Oncology Center (CIO) at the Santa Maria alle Scotte Polyclinic in Siena and president of the NIBIT Foundation.

“The clinical trial that is starting today is also made possible thanks to the important research role played by non-profit associations. In recent years, as the NIBIT Foundation, we have created the first study in the world to combine an epigenetic drug (of the demethylating class of DNA) and ipilimumab in melanoma. The NIBIT-M4 phase Ib trial led in 2019 to the publication of an important work on Clinical Cancer Research. The results obtained in terms of clinical and translational evidence generated on biopsies of the tumors of treated patients – concludes Maio – laid the foundations for the NIBIT-ML1 study “.